Device and Method for Analyzing a Material

ABSTRACT

An apparatus for analyzing a material includes an excitation emission device for generating at least one electromagnetic excitation beam, in particular an exciting light beam, having at least one excitation wavelength, further comprising a detection device for detecting a reaction signal, and a device for analyzing the material on the basis of the detected reaction signal.

This application is a continuation of co-pending U.S. patent application Ser. No. 15/776,544, filed May 16, 2018, which is 35 U.S.C. § 371 National Phase Entry of International Patent Application No. PCT/EP2016/080046, filed Dec. 7, 2016, which claims priority from International Patent Application No. PCT/DE2015/200532, filed Dec. 9, 2015, and from German Patent Application 102016214262.3, filed Aug. 2, 2016, and from German Patent Application 102016215580.6, filed Aug. 19, 2016; all of which are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present intellectual property right relates to a device and a method for analyzing a material. The device described here and the procedure described here can be used for example for the analysis of animal or human tissue, in one embodiment for the measuring of glucose or blood sugar.

BACKGROUND ART

Known methods for analysing a material, in particular for the measurement of blood sugar are described in the following publications, for example:

-   Guo et al.: “Noninvasive glucose detection in human skin-using     wavelength modulated differential laser photothermal radiometry”,     Biomedical Optics Express, Vol, 3, 2012, No. 11, -   Uemura et al.: “Non-invasive blood glucose measurement by Fourier     transform infrared spectroscopic analysis through the mucous     membrane of the lip: application of a chalcogenide optical fiber     System”, Front Med Biol Eng. 1999; 9(2): 137-153, -   Farahi et al.: “Pump probe photothermal spectroscopy using quantum     cascade lasers”, J. Phys. D. Appl. Phys. 2012 and -   M. Fujinami et al.: “Highly sensitive detection of molecules at the     liquid/liquid interface using total internal reflection-optical beam     deflection based on photothermal spectroscopy”, Rev. Sei. Instrum.,     Vol. 74, Number 1 (2003). -   (1) von Lilienfeld-Toal, H. Weidenmüller, M. Xhelaj, A. Mantele, W.     A Novel Approach to Non-Invasive Glucose Measurement by Mid-Infrared     Spectroscopy: The Combination of Quantum Cascade Lasers (QCL) and     Photoacoustic Detection Vibrational Spectroscopy, 38:209-215, 2005. -   (2) Pleitez, M. von Lilienfeld-Toal, H. Mäntele W. Infrared     spectroscopic analysis of human interstitial fluid in vitro and in     vivo using FT-IR spectroscopy and pulsed quantum cascade lasers     (QCL): Establishing a new approach to non-invasive glucose     measurement Spectrochimica acta. Part 'A, Molecular and biomolecular     spectroscopy, 85:61-65, 2012 -   (3) Pleitez, M. et al. In Vivo Noninvasive Monitoring of Glucose     Concentration in Human Epidermis by Mid-Infrared Pulsed     Photoacoustic Spectroscopy Analytical Chemistry, 85: 1013-1020, 2013 -   (4) Pleitez, M. Lieblein, T. Bauer, A. Hertzberg, 0. von     Lilienfeld-Toal, H. Mäntele, W. Windowless ultrasound photoacoustic     cell for in vivo mid-IR spectroscopy of human epidermis: Low     interference by changes of air pressure, temperature, and humidity     caused by skin contact opens the possibility for a non-invasive     monitoring of glucose in the interstitial fluid Review of Scientific     Instruments 84, 2013 -   (5) M. A. Pleitez Rafael, 0. Hertzberg, A. Bauer, M. Seeger, T.     Lieblein, H. von Lilienfeld-Toal, and W. Mäntele. Photo-thermal     deflectometry enhanced by total internal reflection enables     non-invasive glucose monitoring in human epidermis. The Analyst,     November 2014.

SUMMARY

The object of the invention is to specify a device with which a material, in particular an animal or human tissue or a component or ingredient of the tissue, can be analysed particularly simply and cost-effectively.

This object is achieved by, inter alia, a device having the features as defined in claim 1. Embodiments of the device are specified in dependent claims.

Reference is made to the German patent DE 10 2014 108 424 B3, the content of which is referred to specifically, and the content of which this application extends; by this explicit reference made here, the full contents of German patent DE 10 2014 108 424 B3 is therefore also to be regarded as part of the disclosure of this application (“incorporation by reference” for all details of that disclosure). In particular, this reference relates to all the features given in the patent claims as granted. In addition, the reference relates in particular to details of the excitation light beam mentioned there, for example, to the numerical values of the pulse frequencies and wavelengths (wavelength ranges) cited there, and also to the details relating to the measurement of glucose content in the interstitial fluid.

In addition to the subject matter of the claims and exemplary embodiments which are directly and explicitly mentioned at the time of filing, the present PCT property rights application also relates to other aspects, which are listed at the end of the present description. These aspects can be combined, either individually or in groups, with features of the claims cited at the time of filing. These aspects, whether taken alone or combined with each other or with the subject matter of the claims, represent stand-alone inventions. The applicant reserves the right to make these inventions the subject matter of claims at a later date. This can be done in the context of this application or else in the context of subsequent divisional applications, continuation applications (in the USA), continuation-in-part applications (in the USA) or subsequent applications claiming the priority of this application.

In the following, however, the subject matter of the claims mentioned at the time of filing will be discussed first.

A device for analysing a material is provided, with an excitation transmission device for generating at least one electromagnetic excitation beam, in particular an excitation light beam with at least one excitation wavelength, a detection device for detecting a response signal and a device for analysing the material on the basis of the detected response signal.

A major advantage of this device is the fact that it can be used to analyse a material in a very simple and reliable way.

The measurement of concentrations of a given substance in a bodily fluid is also illustrated in the present intellectual property application using the example of glucose in the ISF (interstitial fluid). The various subject matters of the present application are not restricted thereto, however.

Other (bodily and non-bodily) substances can be measured, for example, those describe d in DE 10 2014 108 424 B3 and in the PCT application claiming its priority.

In particular, the methods and devices can also be used for determining drug levels (“drug monitoring”). In the context of this intellectual property protection right, this is under stood to include measuring the concentrations of drugs in the blood or in other fluid-containing spaces of the human or animal body, for example in the blood serum or plasma, saliva, or lymph, and in particular, also non-invasively and in vivo in the interstitial fluid.

In particular, drug level determination can also be used to improve the dosing of drugs with a narrow therapeutic range. Particularly in the case of medicines that can be easily overdosed or under-dosed, the concentrations of which can be easily affected by other medicines or which have a toxic effect above a certain concentration, drug monitoring is a useful technique. An example of an appropriate benchmark to be met is reaching or maintaining a specified effective level and determining the necessary individual drug dosage.

Using the methods and/or devices shown in this protection right, document medically important levels can be determined rapidly or even in real-time, for example of paracetamol, phenytoin, valproic acid, lamotrigine, phenobarbital, flecainide, digitoxin, digoxin, tacrolimus, everolimus, amiodaron, aminoglycoside, theophyllin, vancomycin, lithium, carbamazepine, sirolimus, methotrexate and other materials, wherein in each case different spectroscopic “fingerprints”, i.e. characteristic extrema (in particular, absolute and relative absorption maxima and minima), facilitate the detection and identification of the respective substance.

The device presented in the claims can in each case also be associated with a dosing dev ice for the dosed administration of one or more of the substances mentioned, to allow a control loop to be formed.

It is notable, in particular in connection with the measuring of glucose in the ISF, that the only truely clinically useful results in the evaluation of characteristic extrema have bee n obtained in the middle infrared range, and in particular, if the detection of the absorption maxima and minima in this range is performed with a plurality of relatively closely s paced wavelengths. This is used to compensate the inaccuracy (caused by temperature sensitivity of the laser, noise in the evaluation electronics etc.) so that a sufficiently accurate measurement result is always achieved. With regard to the number of wavelengths to be emitted, reference is made to the patent claims. If three characteristic adjacent extrema of a substance, i.e. (relative or absolute minima and/or maxima) are present, it can be advantageous, for example, if at least ten, preferably at least twenty wavelengths in the interval between the two outer extrema are emitted.

The term light is understood here to mean electromagnetic waves or electromagnetic radiation in the visible range, in the near and far infrared range and in the UV range.

In an exemplary embodiment of the device it is provided that the excitation transmission device is a radiation source, in one embodiment a monochromatic, in particular polarised radiation source or light source, more particularly a laser light source,

-   -   the device has an optical medium, which is in direct contact         with the material, in particular with a first region of the         surface of the material,     -   wherein the excitation transmission device is preferably         arranged in such a way that the emitted excitation beam         penetrates the optical medium and exits the same again at a         predetermined point on the surface of the optical medium, and     -   the device comprises a system for emitting a measuring beam, in         particular a measuring light beam, which is arranged in such a         way that the emitted measuring beam penetrates into the optical         medium and wherein in operation the measuring beam and the         excitation beam preferably overlap at an interface of the         optical medium and the surface of the material at which the         measuring beam is reflected, and     -   the detection device is a device for receiving the reflected         measuring beam which forms the response signal, and/or for         directly or indirectly detecting a deflection of the reflected         measuring beam.

Preferably, the device has an optical medium which is in direct contact with the material, in particular with a first region of the surface of the material, in one embodiment the skin of a human being, wherein for detecting a response signal the detection device detects a parameter change of the optical medium, in particular in a region adjacent to the first region, as a result of the response signal, in particular a deformation and/or density change of the optical medium as a result of a local, time-dependent heating. The optical medium may consist of a material which is optically transparent or transparent to infrared radiation or ultraviolet radiation, in general to the excitation beam and the measuring beam, such as glass, crystal, zinc sulphide (ZnS), zinc selenide (ZnSe), germanium (Ge), silicon (Si) and diamond or a transparent plastic, in one embodiment a polyethylene. A local h eating in response to a transport or transfer of heat from the material to be analysed or from a substance of the material into the optical medium leads to a change therein, for example, a material deformation or thermal stresses or local changes in refractive index, which are detectable.

The material can in one embodiment be the tissue of a living organism, in particular a human being, wherein the material surface can be the skin. Substances in the tissue can then be analysed or measured.

It can also be provided that the detection device has a piezo-element connected to the optical medium or integrated into it, as a detector for detecting a stress, deformation and/or density change.

It can also be provided that the detection device has at least one temperature sensor as a detector for detecting the response signal. This can be arranged directly on the optical medium or in its surroundings, depending on the measuring principle.

Preferably, the device has a system for intensity modulation of the excitation light beam.

The detection device is preferably suitable for detecting a time-dependent response sign al as a function of the wavelength of the excitation light and/or the intensity modulation of the excitation light.

It can also be provided that the excitation transmission device radiates at least one electromagnetic excitation beam into a volume of material, which is underneath a first region of the surface of the material.

Particularly preferably the excitation transmission device comprises two or more transmission elements, in particular in the form of a one-, two- or multi-dimensional transmission element array. This can therefore be implemented as a surface array of transmission elements, or else as a transmission element strip (in one embodiment semiconductor laser arrays or QCL arrays, wherein QCL stands for quantum cascade laser).

It can also be provided that the two or more transmission elements each generate their own electromagnetic excitation beam and radiate this into the volume underneath the first region. The different excitation beams can also be emitted successively, or else at least partially at the same time. The different transmission elements can also be operated with different modulation frequencies at the same time.

The wavelengths of the electromagnetic excitation beams of the two or more transmission elements are preferably different. The wavelengths are preferably chosen in such a way that a substance to be detected in the material to be analysed absorbs radiation of these wavelengths particularly well. Additionally or alternatively, wavelengths or wavelength ranges can also be selected, which the substance to be detected does not absorb, but which are absorbed by other substances (so-called tolerant wavelengths), to distinguish the substance to be analysed from other substances.

In one embodiment the excitation transmission device comprises two or more lasers, in particular in the form of a one- or two-dimensional laser array, wherein a plurality of rows of laser elements can be staggered and arranged offset one behind another in order to save space, in one embodiment in the form of a laser strip and/or two or more light-emit ting diodes, in particular in the form of a one- or two-dimensional diode array, in a depth-staggered manner and offset relative to one another, in one embodiment of a two-dimensional array or a strip. The output beams of the arrays can either have individual beam axes, close together or in parallel, for each beam element, or can have a same beam axis, by means of already integrated sets of optics.

Regarding the structure of the device, it can be provided that the excitation transmission device is directly or indirectly—preferably by means of an adjustment device—mechanic ally fixedly connected to an optical medium, which is in direct contact with the material, in particular with the first region of the surface of the material. Therefore, the excitation transmission device can be aligned and fixed relative to the optical medium as early as the manufacturing stage, or at least before deployment.

For the purpose of mounting and/or alignment or adjustment of an excitation transmission device and/or elements of a detection device, the optical medium can have at least one built-in elevation and/or indentation, such as a bridge, a shoulder, a half-sphere mounted thereon, a mounted block, a cone or a drilled hole, a groove, a hollow or other recess, in or on which the above-mentioned elements (the excitation transmission device and/or elements of a detection device) can be placed, rested on or to which they can be aligned or fixed. It is also possible that aligned matching surfaces be formed on the optical medium by machining or in a casting process

With regard to the device for intensity modulation it can be provided that it comprises a n electrical or electro-mechanical modulation device, which is electrically connected to the excitation transmission device and in particular, electrically controls the same, or is formed by such a device. The modulation device can generate an intensity modulation of the excitation beam, in one embodiment a periodic intensity modulation, also for example in the form of rectangular pulses, a sawtooth function or a sine-wave function or other periodic function.

Alternatively or additionally, the device for intensity modulation can comprise at least one controlled mirror arranged in the beam path, by the control of which the intensity of the excitation beam can be modulated by deflection.

Alternatively or additionally, the device for intensity modulation can comprise at least one layer, which is arranged in the beam path and is controllable with respect to its transparency, or can be formed by such a layer. Therefore, the modulation element can be designed in the form of a transmission element which is controlled with respect to its transmission. The modulation element can generate a plurality of spatially separated light beams from one light beam. It can also be provided in one embodiment that the surface of a sample can be scanned with the modulation element. In one embodiment, the modulation element can be controlled together with the array of light sources/laser sources.

A device for emitting a measuring beam, in particular a measuring light beam, is in one embodiment provided for emitting the measuring beam into the particular area of an optical medium, which is in contact with the first region of the surface of the material.

The device for emitting a measuring beam and the detection device are aligned to each other in one embodiment in such a way that the detection device detects the measuring be am as the time-dependent response signal, after this beam has been reflected at least one e at the interface of the optical medium that is in contact with the material, in particular with the first region of the surface of the material.

With a view to ease of assembly, it is advantageous if the device for emitting a measuring beam and/or the detection device and/or the excitation transmission device are directly fixedly mechanically connected to the optical medium and/or are coupled to the same by means of one or more fibre-optic cables.

Embodiments are also possible, in which the optical medium directly supports an imaging optics and/or an imaging optics is integrated into the optical medium.

In addition, embodiments are conceivable in which the surface of the optical medium has a plurality of partial faces inclined towards each other, at which the measuring beam, in particular the measuring light beam, is reflected multiple times.

Embodiments can also be provided, in which one or more mirror surfaces for reflection of the measuring beam, in particular the measuring light beam, are provided in or on the optical medium.

With a view to a compact design, it is conceivable that the excitation transmission device and/or the device for emitting the measuring beam and/or the detection device are directly attached to each other or to a common support. In one embodiment, the various dev ices can be fixed to the support by welding or gluing or by screws or a snap-in connection, wherein an adjustment facility can be provided, either during assembly or else at a later time, by means of an adjusting screw or other mechanical adjustment device. In particular, the device for emitting the measuring beam and/or the detection device should be, or capable of being, easily aligned with respect to each other. Therefore, it can be useful to attach these two devices directly to the optical medium. The device for emitting the measuring beam and/or the detection device, given suitable guidance of the measuring beam, can also be arranged next to each other on the same side of the optical medium and on a common support, in one embodiment attached to a common printed circuit board or a common semiconductor, or else implemented as a common integrated semiconductor device, in one embodiment as a common integrated semiconductor component. This support can then be adjusted as a unit relative to the optical medium, in a particular embodiment, even without further changing the relative position between the device for transmitting the measuring beam and/or the detection device.

The support is preferably formed by a printed circuit board, a metal plate or plastic plate or a housing or part of a housing of the device.

It can also be provided that the excitation transmission device comprises an integrated semiconductor device, which has one or more laser elements and at least one micro-optical component and preferably an additional modulation element. The above-mentioned elements can be manufactured, in one embodiment etched, jointly from one semiconductor blank or at least accommodated in a common housing.

It can also be provided that the modulation element has at least one element, in particular a mirror, which is movable relative to the rest of the semiconductor device and is controllable with respect to its position. This can be controlled by means of a MEMS device.

It can also be provided that the modulation element has a layer which is controllable in terms of its radiation permeability.

It can also be provided that the modulation element has an electronic control circuit for the modulation of the one or more laser elements. In one embodiment the modulation element can be constructed in such way that it varies the excitation beam in a time-dependent manner by interference, phase offset/path offset or a polarising filter device or other known modulation mechanisms.

The micro-optical component or components can be mirrors or lenses that are either integrated into the semiconductor component or made from it in a subtractive process, in particular by etching.

The described device for analysing a material can determine a measurement value of a material concentration, in one embodiment a glucose concentration. The device can have an interface to a device for displaying measurement values and their analysis, for example by means of a colour code for a user of the device, and/or to a dosing device for a substance which can be dispensed into the material, in particular the tissue or, more generally, the body of an organism. The device can also directly comprise such a dosing device. In this case, the device can also have a system for detecting or analysing the material surface, in one embodiment the skin surface or in another embodiment the ocular surface or iris of a living being, which enables the identification of a person or a living being based on a comparison with reference data and can therefore be used to ensure that appropriate reference values and/or calibration values are provided for the analysis of the material and the control of the dosing device. Determined characteristic values of the material surface, in one embodiment a fingerprint or the structure of an iris of the eye, can, in addition to identifying and authenticating a person, e.g. against a database, also be used for encrypting the communication of status values and controlling the dosing device which, encrypted or unencrypted, can in principle be originated from the database. In one embodiment the dosing device can be equipped with a sensor to determine a fill level of a substance to be dispensed, such as in one embodiment insulin and/or glucagon, heparin or an anaesthetic, and can have a device for transmitting the fill level to the device for material analysis and/or directly to the database.

In addition, the device can have an interface, in one embodiment a radio interface to the database, to which the measurement values can be sent and which can process the data. The database can be created in such a way that it processes and stores the data from a plurality of patients, that is, in one embodiment also the data from a plurality of similar de vices for analysing a material, and in one embodiment it also controls individual dosing devices for dispensing substances. The database can also further process the measured data relating to the analysed material and determine derived analysis results, such as any trend in the values, first and second time derivatives, minima, maxima, standard deviations of material quantities or concentrations, blood sugar values or other physiological val ues of patients, compare them and derive signals from them, which in one embodiment also includes alarm signals. The fill level of the dosing device can also be detected and processed by the database in order to determine, in one embodiment, a temporal extent of the fill level or the need for refilling and to signal this directly to the patient's device or to a service facility. For this purpose, the database can be connected to a communication device in a service facility, in one embodiment in a hospital or a medical practice. For the purpose of sending data from and/or to a database, the device can in one embodiment be connected to a mobile device or a pager by means of a radio link, in one embodiment Bluetooth or WLAN or Wifi, or other transmission methods. The device can also be directly equipped with a WLAN interface and an internet client.

The subject matter also relates to a method for analysing a material, wherein in the method at least one electromagnetic excitation beam with at least one excitation wavelength is generated with an excitation transmission device by the successive operation or the at least partially simultaneous operation of a plurality of laser emitters of a laser light source, and a response signal is detected with a detection device and the material is analysed on the basis of the detected response signal. In the method, the thermal diffusivity in the material and the temporal evolution or waveform of the response signal can be used to characterize the nature of the material or a spatial distribution of a substance in the material or to characterize the depth at which the excitation beam is absorbed.

In one embodiment it can be provided that using different modulation frequencies of the excitation transmission device, response signals, in particular temporal response signal waveforms or patterns, can be successively determined and that a plurality of response signal waveforms or patterns at different modulation frequencies can be combined with each other and that, in particular, specific information for a depth range under the surface is obtained from this.

It can also be provided that response signal waveforms or patterns are determined at different modulation frequencies for different wavelengths of the excitation beam and from these, in particular specific information is obtained for each depth range under the surface. When using a plurality of modulation frequencies of the pump beam at the same time, it is possible, for example, to resolve the detected signal into its frequencies using an appropriate analysis method, for example, an integral transformation, such as a Fourier transformation; the FT would only filter out the signal that corresponds to the desired frequency.

It can also be provided that an optical medium is brought into direct contact with the material, in particular with a first region of the surface of the material, the emitted excitation beam is generated and, in particular, emitted with the excitation transmission device in such a way that it penetrates into the optical medium and exits it again at a predetermine d point on the surface of the optical medium, that a measuring beam, in particular a measuring light beam, is generated with a device for emitting a measuring beam in such a way that this beam penetrates the optical medium and that in particular, in operation, the measuring beam and the excitation beam overlap at an interface of the optical medium and the surface of the material at which the measuring beam is reflected, and that a reflected measuring beam which forms the response signal is measured and/or the deflection of the reflected beam is directly or indirectly detected with the detection device.

One aspect of the method is the focussing of the measurement of the response signal on selected depth ranges underneath the (distance intervals from the) material surface. The thermal wavelength d has the greatest influence on the depth range measured with the method. It is defined as d=√(D/(π*f)), where D is the thermal diffusivity of the sample (here for example, skin) and f is the modulation frequency of the excitation beam. Literature on the thermal diffusivity of skin:

-   U. Werner, K. Giese, B. Sennhenn, K. Piamann, and K. Kolmel,     “Measurement of the thermal diffusivity of human epidermis by     studying thermal wave propagation,” Phys. Med. Biol. 37(1), 21-35     (1992). -   A. M. Stoll, Heat Transfer in Biotechnology, Vol 4 of Ad-vances in     Heat Transfer, J. P. Hartnett and T. Irvin, eds. (New York,     Academic, 1967), p 117.

In one embodiment, to eliminate response signals from the topmost layers of the material, changes in the measurements compared to previous measurements can be used, in case the measurements in the top layers change more or less slowly in comparison to other, deeper layers.

This can be the case in an embodiment in measurements on human skin, where the topmost layers of the skin undergo virtually no exchange with the lower layers and therefore physiological parameters change very little. The time derivative of measurements can al so be applied to provide response signals to exclude the signals from the topmost layers of the skin. Thus the measurement, or at least the evaluation, can be limited to or focused on the interstitial fluid in the skin.

It can also be provided that depending on a material concentration identified in the material, a dosing device for dispensing a substance, in particular into a patient's body, is controlled and/or an acoustic and/or visual signal is output and/or a signal is output to a processing device via a wireless connection. In this case, in addition to a currently determined measurement a temporal development or evolution of the measurement values, a derivative of the measurement value, average values of the measurements, maxima, minima, a standard deviation and predefined thresholds for measurement values can be taken in to account and combined with the current measurement value. In one embodiment, the processing device can be a database or connected to a database, which collects and processes data from a plurality of patients. The database can be either directly connected to a control system of the device or be remote from and connected to it via a communication interface.

To obtain increased security when operating a dosing device, in particular for insulin, it can be provided that this is operated locally or from a database under the control of a preset standard procedure with preselected quantity deliveries at times that are or can be specified, and that by means of the above-described device meaningful deviations from p reset delivery values can be determined that are used for the correction and improvement of the control of the dosing device. In this way, even in the event of a failure of the dev ice at least a normal or emergency operation of the dosing device is guaranteed.

In the method according to the invention it can also be provided that the measurement, which comprises the detection of the response signal at one or a plurality of modulation frequencies or in a time-resolved manner after a transmission pulse and at one or more wavenumbers, is repeated successively at different entry angles/incidence angles of the excitation beam, and that the results are combined with each other, in particular subtracted from each other, to reduce or eliminate the effects of the upper layers of the skin. At least one of these angles of incidence can be at or near 90 degrees, in other words a perpendicular entry of the excitation beam into the skin/the material to be analysed.

This concept is based on the consideration that at a flatter, smaller angle of incidence the excitation signal travels a longer distance in the upper and uppermost layers of the skin than in the case of a steeper, larger angle of incidence. This means that at a smaller angle of incidence a greater proportion of the excitation radiation is also absorbed in the upper layers of the skin than is the case for a larger angle of incidence, so that the influence of the upper layers of the skin are isolated, at least to some extent, and can be eliminated by combining the measurement results at different angles of incidence.

Advantageous for this process is the fact that the region in which the excitation radiation is absorbed is not noticeably shifted parallel to the surface, in particular to the skin sur face, due to the change in the angle of incidence. Angular changes can be made between the different entry angles/incidence angles of at least 5 degrees, in particular at least 10 degrees, more particularly at least 20 or at least 30 degrees. The angular changes can be achieved by refraction or reflection of the excitation beam outside or inside the optical medium, within the medium for example by selective modification of the refractive index, for example by applying an electrical voltage to the crystal according to an electro-optical effect.

In the context discussed above a method can also be provided in which the measurement comprises the detection of the response signal at at least one modulation frequency, which is selected such that the resulting thermal diffusion length, which is a function of the modulation frequency, allows a sufficiently deep scanning of the sample. In addition, as part of the depth profiling, further modulation frequencies can be used for characterizing the surface or near-surface layers of the material to be examined, for example, the upper layers of the skin in the case of the skin, and thus also for the elimination of irrelevant influences of the same (for example, contaminations, absorption of irrelevant materials).

In addition, when measuring the response signal at at least one or a plurality of modulation frequencies, the phase angle of the response signal can also be taken into account in the evaluation process. Amplitudes and phase angles of one or more frequencies can thus be combined, for example by subtraction of the amplitudes and/or calculation of phase-dependent signal responses.

In the methods discussed, it can also be provided that during the measurement the scanning beam is operated at least some of the time in the wavenumber range between 5000/c m and 16000/cm, in particular some of the time between 15500/cm and 16000/cm, and more particularly some of the time between 15700/cm and 16000/cm.

It can also be provided that in the case of a measurement in which the excitation beam is successively adjusted to different wavenumbers and/or wavenumber ranges, at least 5%, in particular at least 10%, more particularly at least 30%, more particularly at least 50% of the wavenumber range or wavelength range covered is located in areas of the spectrum which are insensitive to the material to be identified, in particular glucose.

In the context of the present application, a region or a point of the spectrum is referred to as insensitive with respect to a material to be identified contained in a sample, if an absorption intensity of the sample in the region or at the point of the spectrum is independent of the quantity and/or concentration of the material in the sample. This usually means that the material has no definable absorption bands in this region of the spectrum.

It can also be provided for a maximally undistorted and accurate measurement that, in order to take account of the absorption characteristic of the sample or the tissue which is independent of the glucose concentration, at least one or two wavenumber ranges or wavelength ranges without a significant absorption by glucose are provided, in which the ab sorption is measured.

It can be provided that at least one of the wavenumber ranges is between 1610 and 1695 cm−1 (amide 1).

It can also be provided that at least one of the wavenumber ranges is between 1480 and 1575 cm−1 (amide 2).

It can also be provided that to perform a measurement, a depth range to be investigated in the sample is first selected, and that the excitation beam is controlled thereafter in such a way that between time intervals (excitation pulses) in which the excitation beam is emitted, there is always at least one period which corresponds to the diffusion time required by a thermal wave to traverse the distance between the depth range to be investigated in the sample and the sample surface.

This allows certain specified materials to be detected at specific depths or depth ranges under the surface of the sample, as well as the concentration profile as a function of the depth. In the area of cosmetics or pharmaceuticals it is thus possible, for example, to determine the penetration depth or the penetration velocity of a material into the skin, which passes through the skin surface.

It can also be provided that the temporal intensity response of the absorption is measured after the end of each time interval in which the excitation beam is emitted. Alternatively, or in addition to the absorption intensity, the phase position of the response signal can therefore be taken into account in the analysis.

It can also be provided that to control a laser for generating the excitation beam, a series of stored equidistant or non-equidistant setting values can be successively adjusted, each of which determines a wavenumber/wavelength of the laser and among which in particular at least 3, more particularly at least 5 wavenumbers/wavelengths of absorption maxima of a material to be identified are included, (lookup table).

It can also be provided that before and/or during and/or after a measurement, the mechanical pressure and/or the force per unit area is detected, with which the optical medium, in which the scanning beam is reflected, is pressed against the sample. This enables effects of the pressure on the sample or the optical medium to be eliminated from the measurement results or to be taken into account during the analysis.

It can also be provided that before and/or during and/or after a measurement, the humidity of the ambient air and/or moisture content of the sample or the humidity of the upper layers or the surface of the sample is determined. This enables effects of the moisture in the sample or in the measuring device to be eliminated from the measurement results or to be taken into account during the analysis.

The invention also relates to a method for analysing a material, wherein in the method at least one electromagnetic excitation beam (SA) with at least one excitation wavelength is generated with an excitation transmission device by the successive operation of one or more, or by the at least partially simultaneous operation of a plurality of laser emitters of a laser light source, a response signal (SR) is detected with a detection device and on the basis of the detected response signal (SR) the material is analysed.

The successive operation of one or more, or the at least partially simultaneous operation of a plurality of laser emitters, can be used to generate the different wavelengths, which can be located at characteristic wavelengths of a material to be identified in the material, for example at or in the vicinity of absorption maxima.

The invention also relates to a method in which the temperature of the laser emitter(s) of the excitation transmission device and/or the temperature of the detection device, in particular of an optical medium and/or a detection radiation source and/or an optical sensor, is kept constant during the analysis, in particular is kept constant at a specified temperature, more particularly at a specified temperature above the temperature of the human body, more preferably above 37 degrees Celsius, more preferably above 38 or 40 degrees Celsius.

By this measure, the effect of temperature on the measurement can be kept to a minimum. Also, any heating as a result of the bodily contact can be avoided if the measuring de vice is kept at a temperature at or above the body temperature, at least during the measurement. This can be effected by a temperature control system with a heating element and one or more sensors.

The invention relates to a method in which during the analysis, the temperature of the laser emitter(s) of the excitation transmission device and/or the temperature of the detection device, in particular of an optical medium and/or a detection radiation source and/or an optical sensor, is detected and taken into account in the evaluation of the analysis by combining or associating the measurement results with temperature correction values.

With this method, the temperature effects are taken into account by computation.

A further embodiment of the invention can provide that the material, in particular a body part, in particular a finger, is pressed against an optical medium which is part of the detection device, that the pressure exerted on the medium by means of the pressed-on body part is detected, and that the excitation transmission device is turned on depending on the detected pressure on the medium, and/or it is turned off depending on a reduction in the pressure, in particular below a specific threshold.

In this way, a pressure sensor is used to determine whether the measuring device is currently being used and/or whether the optical medium is currently covered by an object, on which a measurement is being made. Only in this case is the excitation transmission device enabled. This prevents a larger proportion of the excitation beam from escaping via the optical medium or in any other manner into the outside environment, if there is no measurement/analysis taking place.

It can also be provided that the material, in particular a part of the body, in particular a finger, is pressed against an optical medium which is part of the detection device, that a darkening of the medium in the area of the pressed-on body part is detected and that the excitation transmission device is turned on by a darkening of the medium and/or turned off by an increase in the luminosity in the medium, in particular above a certain threshold

It is therefore possible using a luminosity sensor/photodetector to determine whether the measuring device is currently being used and/or whether the optical medium is currently covered by an object on which a measurement is being made. Only in this case is the excitation transmission device enabled.

It can also be provided that the material, in particular a body part, in particular a finger, is pressed against an optical medium which is part of the detection device, that a moisture level of the medium in the area of the pressed-on part of the body is detected, and that the excitation transmission device is turned on upon reaching a specified moisture level on the medium and/or is turned off by a reduction in the moisture level, in particular below a certain threshold.

Thus, in this configuration a moisture sensor is used to determine whether the measuring device is currently being used and/or whether the optical medium is currently covered by an object, on which a measurement is being made. Only in this case is the excitation transmission device enabled.

A further embodiment of the invention can provide that during the implementation of the method a body part pressed onto the optical medium is affixed to the medium, in particular is fixed by clamping the body part to the medium, gluing the body part to the medium, adhesion of the body part to the medium or by vacuum suction of the body part to the medium.

Thus, more stable measurement conditions are created, so that a certain minimum time is available for the measurement. The measuring accuracy and reliability is thus increased.

It can also be provided that the excitation beam (SA) is emitted with at least two or more than two excitation wavelengths or groups of excitation wavelengths, wherein a first excitation wavelength or group of excitation wavelengths enables the identification of the substance to be identified in the material, while at least one additional excitation wavelength or group of excitation wavelengths enables the identification of a reference substance which is different from the substance to be identified, and that for the at least two different substances profiles are determined with regard to their density distribution over the depth of the material and combined with each other, and wherein in particular a depth profile, or at least one or more parameters of a depth profile, of the reference substance in the material is known.

This method uses the fact that the depth profile of a plurality of substances can be deter mined independently of each other by a suitable choice of the excitation wavelengths. If a depth profile of a substance is known, which is introduced into the skin or is present there anyway with a profile in accordance with the physiological regularities, then the depth dimension of a different measured substance can be calibrated from it.

It can also be provided that the excitation beam is modulated (SA), preferably successively modulated with different modulation frequencies, wherein response signals for different modulation frequencies are detected or a time response of the characteristic signal in the event of a change in intensity of the excitation beam, in particular its periodic activation and/or deactivation, is analysed.

This measuring method allows the determination of the depth dimension from which the response signals to the excitation beam arise, without the use of different modulation frequencies or with just a small number of modulation frequencies. The response signals originating from different depths can be determined on the one hand from the dependence of their intensity on the modulation frequency, but also from the time characteristic of the response signals to a change of intensity of the excitation beam (e.g. when it is turned off). These characteristics of the response signals are measured phase-sensitively during a periodic intensity change of the excitation signal (e.g. pulsing, turning on and off).

Signals from smaller depths follow the intensity changes of the excitation beam more rapidly than signals from greater depths.

It can be provided that the excitation beam (SA) is modulated by controlling a laser device (100) which generates the excitation light beam.

A further design of the invention can provide that the excitation beam is modulated with between 0 and 10 modulation frequencies, preferably with between 0 and 5 modulation frequencies, preferably with between 1 and 3 modulation frequencies, more preferably with only one modulation frequency, and the time characteristic of the response signal, in particular a phase-sensitive characteristic of the response signal, is analysed.

It can also be provided that the duty cycle of the excitation beam (SA) is between 3% and 60%, preferably between 3% and 50%, more preferably between 3% and 7%.

A further configuration of the invention can provide that the power density of the excitation beam (SA) at the surface of the analyte is less than 5 mW/mm2, in particular, less than 2 mW/mm2, more particularly less than 1 mW/mm2.

This avoids any heating of the material to be analysed and the laser light source is protected.

It can also be provided that the optical medium of the detection device is brought into contact with a body part, in particular with a finger and/or with a vessel carrying a dialysate and/or with a vessel of a dialysis unit carrying blood and that, in particular, one or more excitation wavelengths are selected that enable the detection of urea, cholesterol, albumin, protein, creatinine, lactates or phosphates.

This means that both the dialysis process can be monitored, and dialysis patients can be continuously monitored with the measuring device according to the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 24 schematically show different elements of the device and its elements, in some cases in different embodiments.

DETAILED DESCRIPTION

FIG. 1 shows an exemplary embodiment of a device 10 for analysing a material 101. The material 101 is preferably placed directly on an optical medium 108, which can be designed as an optically transparent crystal or glass body. The device for analysing the material 101 is used for example to measure the glucose or blood sugar content in a fluid, such as in one embodiment blood, and for producing a glucose or blood sugar level indication BZA.

FIG. 1 shows an exemplary embodiment of a device 10 for analysing a material 101. The material 101 is preferably placed directly on an optical medium 108, which can be designed as an optically transparent crystal or glass body or plastic body or plastic crystal. The device for analysing the material 101 is used for example to measure the glucose or blood sugar content in a fluid, such as in one embodiment blood, and for producing a glucose or blood sugar level indication BZA.

The device comprises an excitation transmission device 100 for emitting one or more electromagnetic excitation beams SA, preferably in the form of excitation light beams with one or more excitation wavelengths, into a volume 103 which is located in the material 101 below a first region 102 of the surface of the material. The excitation transmission device 100 is also referred to in the following as “excitation light source” 100 for brevity. The excitation light source 100 can be a laser which is tunable with respect to its wavelength, in particular a tunable quantum cascade lasers; it is preferable, as will be explained below, to use a light source strip or a light source array with at least two single emitters, in particular semiconductor lasers, each of which emits a specified individual wavelength.

In addition, a device 104 for the intensity modulation of the excitation light beam or beams SA is provided, which is preferably formed by a modulation device for the excitation light source, in particular for controlling it, and/or by at least one controlled mirror arranged in the beam path and/or by a layer, which is arranged in the beam path and is controllable with respect to its transparency.

In addition, the device has a system 105 for emitting an electromagnetic measuring beam 112, in particular a measuring light beam, which is reflected, preferably totally reflected, at the interface GF between the material 101 and the optical medium 108.

A detection device 106 is used for the detection of the reflected measuring beam 112, which forms a time-dependent response signal SR; the amplitude of the response signal SR is influenced by the wavelength of the excitation light SA and the intensity modulation of the excitation light SA, as will be explained in more detail below by means of examples.

The amplitude of the measuring signal depends on the wavelength of the excitation beam, the absorption properties of the sample and the thermal properties, in particular the thermal diffusivity and thermal conductivity of the sample and of the optical element. In addition, the coupling of the thermal signal from the sample into the optical element also plays a role.

A device 107 for analysing the material evaluates the detected response signals SR and in one embodiment generates a glucose or blood sugar level indication BZA.

Hereafter, the operation of the device 10 in accordance with FIG. 1 and in this connection, an example of a method for analysing a material 101 will be described in more detail for the case in which the material 101 to be analysed is human or animal tissue, and as part of the analysis of the material a glucose or blood sugar level indication BZA is to be determined.

With the device 105 an electromagnetic measurement beam 112, which is preferably a light beam in the visible wavelength range or an infrared light beam, is irradiated into the optical medium 108; this measurement beam 112 impinges on the interface GF below the first region 102 of the surface of the tissue. At the interface GF the measuring beam 112 is reflected and reaches the detection device 106, which measures the reflected measurement beam 112.

At the same time, one or more excitation beams SA, which are preferably infrared beams, are generated with the excitation light source 100. The wavelength of the infrared beams is preferably in a range between 3 μm and 20 μm, particularly preferably in a range between 8 μm and 11 μm.

The excitation beams SA are intensity- or amplitude-modulated with the device 104 for intensity modulation. In one embodiment short light pulses are generated with the device 104 for intensity modulation, preferably with a pulse frequency of between 1 kHz and 10 MHz, more preferably between 1 kHz and 3 MHz, or else pulse packets (double or multiple modulation), preferably with envelope frequencies of 1 Hz-10 kHz.

The modulated excitation beams SA are coupled into the optical medium 108 and after passing through the interface GF arrive in the volume 103 within the tissue.

The wavelength of the excitation beams SA—with a view to the example of blood glucose measurement explained here—is preferably chosen such that the excitation beams SA are significantly absorbed by glucose or blood sugar. For measuring glucose or blood sugar the following infrared wavelengths are particularly well suited (vacuum wavelengths): 8.1 μm, 8.3 μm, 8.5 μm, 8.8 μm, 9.2 μm, 9.4 μm and 9.7 μm. In addition, glucose-tolerant wavelengths can be used, which are not absorbed by glucose, in order to identify other substances present and allow for excluding their effect on the measurement.

Due to the absorption of the excitation beams SA in the tissue in the region of the volume 103, a local temperature increase is induced, which triggers a heat transfer and thermal waves and thereby also pressure waves in the direction of the interface GF; due to the resulting temperature and pressure fluctuations at the interface GF, the refractive index and/or the deformation, microstructure and the reflection behaviour are modulated in the region 102 and/or in the reflection region of the interface GF, and the beam path of the measuring beams 112 is affected.

If it is assumed, for example, that without excitation beams SA the alignment between the system 105 and the detection device 106 is optimal and a maximum received power is detected by the detection device 106, then due to the absorption of the excitation beams SA in the region of the volume 103 and due to the heat transport and the pressure waves, an (at least temporary) change in the amplitude or, in the case of a periodic modulation, the phase of the reflected measuring beam 112 can be induced, or an intensity modulation of the reflected measurement beam 112 can occur. The extent of the intensity modulation depends on the wavelength of the excitation beams SA (because of the necessary absorption in the tissue) and on the pulse frequency of the excitation beams SA (due to the temperature transport and the pressure waves from the tissue interior in the direction of the interface GF) and on the thermal properties of the sample and the medium.

The change in the reflection of the measuring beam 112 and/or the time-dependent change in the response signal SR is quantitatively acquired by the detection device 106, and the detection result D reaches the device 107.

On the basis of previously carried out calibration or comparison measurements, which in one embodiment are stored in a memory 107 a of the device 107 in the form of comparison tables or comparison curves, the current concentration of glucose or blood sugar within the tissue or within the volume 103 can be deduced and a corresponding glucose or blood sugar indication BZA can be produced. The comparison tables or comparison curves may have been created, for example on the basis of glucose or blood sugar levels which were determined based on blood samples.

Particularly preferred embodiments and variants of devices 10 for analysing a material 101 are described below with reference to FIGS. 2 to 10.

The excitation transmission device 100 for emitting the excitation light beam or beams can be designed as an array, as shown in FIG. 2. The array has at least 5, advantageously at least 10, more advantageously at least 15 or at least 50 or 100 individually controllable emitters 100 a for monochromatic light in the absorption spectrum of a material to be analysed.

The array preferably generates beams with monochromatic light with one or more, particularly preferably all of the following wavelengths (vacuum wavelengths): 8.1 μm, 8.3 μm, 8.5 μm, 8.8 μm, 9.2 μm, 9.4 μm and 9.7 μm and if desired, in addition glucose-tolerant wavelengths.

The device 105 for emission of the measuring light beam 112 and the detection device 106 can be arranged separately from the optical medium 108, as shown in FIG. 1. With a view to a minimal space requirement and minimal installation effort, it is regarded as advantageous if the device 105 for the emission of the measuring light beam 112 and the detection device 106 108 are mounted directly on the optical medium, preferably on opposite surface sections 108 a and 108 b of the optical medium 108, as FIG. 3 shows.

It can be provided that the excitation device/excitation light source 100 is permanently mechanically connected to the optical medium 108 either directly or by means of an adjustment device 109. The adjustment device 109 preferably allows an adjustment of the distance of the excitation light source 100 from the optical medium 108, and/or an adjustment in the beam longitudinal direction and/or an adjustment in a plane perpendicular thereto (see FIG. 4).

As shown in FIGS. 3, 4, 6, 7 and 8, the device 105 can be provided for emission of the measuring light beam 112 into the region of the optical medium 108 that is in contact with the first region 102 of the material surface. Such an arrangement allows the measuring light beam 112 to be irradiated at a flat angle and a total internal reflection to be induced at the interface of the optical medium 108 with the material 101.

By injecting the radiation at a flat (small) angle (to the sample surface), the mirage deflection, analogously to the known photothermal ‘Bouncing Method’, can be made more effective and at the same time the deformation-induced deflection of the measuring beam can be reduced. The angle between the sample surface and the measuring beam in one embodiment can be selected to be less than 20 degrees, less than 10 degrees, in particular less than 5 degrees, more particularly less than 2 degrees or 1 degree, in order to exploit this effect.

Conversely, by providing the irradiation at steeper (larger) angles (to the material surface), by analogy to the known photothermal ‘Bouncing Method’ the deflection can be made more effective and at the same time the mirage-effect related deflection of the measuring beam can be reduced. The angle between the material surface and the measuring beam in one embodiment can be selected to be greater than 20 degrees, greater than 30 degrees, in particular greater than 45 degrees, more particularly greater than 60 degrees or 70 degrees, to exploit this effect.

See related literature:

-   M. Bertolotti, G. L. Liakhou, R. Li Voti, S. Paolino, and C.     Sibilia. Analysis of the photothermal deflection technique in the     surface refection theme: Theory and Experiment. Journal of Applied     Physics 83, 966 (1998)

The device 105 for emitting the measuring light beam 112 and/or the detection device 106 for detecting the measuring light beam 112 and/or the response signal SR, can be mechanically connected to the optical medium 108 in a supportive manner either directly or by means of an adjustment device, and/or coupled thereto by means of one or more fibre-optic cables 120.

It can also be provided, as shown in FIG. 6, that the optical medium 108 directly supports an imaging optics 128 and/or an imaging optics 129 (in each case) in the form of a lens or other reflection or refraction means, and/or that an imaging optics is integrated into the optical medium 108. The imaging optics can, however also be integrated into the excitation transmission device or the device for generating the measuring beam, for example, in the form of a lens or other reflection or diffraction element, if these are designed as integrated components and/or as a semiconductor component. The imaging optics can in one embodiment be subtractively formed from the same semiconductor element by etching as the respective integrated circuit, which has a radiation source for the excitation or measuring beam.

It can also be provided, as shown in FIG. 7, that the surface of the optical medium 108 has a plurality of partial faces 110, 111 inclined towards each other, at which the measuring light beam 112, is reflected or refracted multiple times.

It can also be provided, as shown in FIG. 3, that in or on the optical medium 108 one or more mirror surfaces 113, 114 are provided for reflecting the measuring light beam 112 (and therefore the response signal SR.) These mirror surfaces can be formed by inhomogeneities within the optical medium 108 or by its outer surfaces or by means of, for example, metallic or metallic coated mirror elements that are integrated/fitted/cast-in or mounted on the optical medium. This extends the optical path of the measuring light beam 112 in the optical medium 108 until its entry into the detection device 106, so that in the case of reflection at the region of the surface of the medium 108, which is in contact with the first region 102 of the material surface, a response signal-dependent deflection of the measuring light beam 112 within the optical medium 108 is increased. The deflection can then be detected in the detection device 106 as an absolute deflection.

The detection device 106 can have a plurality of optically sensitive surfaces, such as optically sensitive semiconductor diodes, or else a plurality of staggered openings 116, 117, 118 in a connector body 119 (FIG. 5), at which individual fibre-optic cables 120 end (FIG. 4), into which the light of the measuring light beam 112 is coupled depending on its deflection. The fibre-optic cables 120 are then connected to a connector body 119, which can be fixed to the optical medium 108, and direct the light to the part of the detection device 106 arranged at the end of the fibre-optic cable 120 (FIG. 4). The connector body 119 is then, in the same way as the fibre-optic cable 120, also part of the detection device 106 for detecting the measuring light beam.

For the sake of completeness, it should be noted that the excitation transmission device can also send the excitation to the material surface either as a whole or section by section by means of one or more fibre-optic cables, and in one embodiment the excitation transmission device can be directly coupled to one or more fibre-optic cables, which are coupled to the optical medium.

It can also be provided, as shown in FIG. 8, that the excitation transmission device 100, the device 105 for emitting the measuring light beam 112, and the detection device 106 are directly attached to each other or to a common support 121. The support can be formed by a plastic part, a printed circuit board or a metal sheet, which is mounted in a housing 122. The support, which in FIG. 8 is formed with a U-shaped cross section, can then at least partially surround the optical medium 108 in one embodiment. The optical medium can be attached to the support and adjusted relative to it.

The support can also be formed by the housing 122 itself or a housing part.

It can also be provided that the device with the housing 122 can be fastened to the body 123 of a person, wherein the excitation transmission device 100 for emitting one or more excitation light beams SA, the device 105 for emitting the measuring light beam 112 and the detection device 106 for detecting the time-dependent response signal SR are arranged and configured in such a way that the side that is suitable for performing the measurement (with a measuring window transparent to the excitation radiation) of the device is located on the side of the device facing away from the body, so that the material to be analysed can be measured on the side 124 of the housing 122 facing away from the body 123. In relation to this, FIG. 8 shows that the housing 122 is attached to the body 123 of a person by means of a belt 125 belonging to the housing 123, in one embodiment being in the form of a bracelet on a wrist. On the opposite side 124 from the wrist, the housing then has a window which is transparent to the excitation light beam SA, or the optical medium 108 is fitted directly into the outwards facing side 124 of the housing and itself forms the surface of some sections of the housing.

As shown in FIG. 8, a fingertip 126 shown schematically by a dashed line can then be placed on the optical medium 108 and measured.

The optical medium 108 can be attached within the housing 122, in the same way as the support 121, or else directly attached to the housing 122. The optical medium 108 can also be directly connected to the support 121, wherein an adjustment device 127 should be provided for the relative positioning of the support 121 with respect to the optical medium.

It is also conceivable to attach the excitation light source 100, the device 105 and the detection device 106, or even just one or two of these elements, directly to the optical medium 108 and the other element or elements to the support 121.

Through the optical window in the housing 122 and/or through the optical medium 108, other parameters of the material surface or the positioned fingertip 126 can be measured, such as in one embodiment, a fingerprint. For this purpose, in the housing an optical detector 130 in the form of a camera, for example, can be fastened to the support 121, which records a digital image of the material surface through the optical medium 108. This image is processed within a processing unit 107, which can be directly connected to the detection device and also to the excitation transmission device, in the same way as the measurement information by the detection device 106. The processing device can also perform control tasks for the measurement. It can also be at least partially separated and remote from the remaining parts of the device and communicate with these by means of a wireless connection.

The image data from the camera 130 can thus be further processed inside the housing, or via a radio link even outside the housing, and compared with a personal identity database to retrieve calibration data of the identified person.

This type of calibration data can also be stored for remote retrieval in a database, in one embodiment, a cloud. The measurement data from the detection device 106 can also be further processed both within and outside of the housing.

If data are processed outside the housing, then the resulting data should preferably be sent back to the device within the housing by radio to be displayed there.

In either case, a display can be provided on the housing 122, which advantageously can be read through the optical window, and in one embodiment also to some extent through the optical medium. The display can also project an optical indicator through the optical window onto a display surface and can have a projection device for this purpose. The display can be used in one embodiment to display a measurement or analysis result, in particular a glucose concentration. The information can be output in one embodiment via a symbolic or colour code. By means of the display or a signalling device parallel thereto, in one embodiment a proposal for an insulin dose can be presented, dependent on other patient parameters (e.g. insulin correction factor), or a signal can be transmitted automatically to a dosing device in the form of an insulin pump.

The connection of the device to and from an external data processing device 131 can be implemented using all common standards, such as fibre-optic cables, cable, wireless (e.g. Bluetooth, WiFi), or else ultrasound or infrared signals.

FIG. 9 shows a modulation device with a controller 132, which activates the excitation transmission device in a modulated manner. Both the controller 132 and the detection device 106 for the measuring light beam are connected to the evaluation device 107.

FIG. 10 shows an excitation light source 100, in front of which a mirror device, in particular a mirror device driven by a MEMS (micro-electromechanical system) 135 is arranged, with one or more micro-mirrors 133, 134, such as those known from optical image projector technology, for the occasional deflection of the excitation light beam in a deflection direction 136.

FIG. 11 shows an excitation light source 100, in front of which an optical layer 138 with a transmission that can be controlled by means of a control device 137 is arranged in the excitation light beam, in one embodiment with LCD cells.

In summary, it should be noted that the device described in the present case and the described measuring method, in particular in its application to glucose measurement to patients, spares them the painful and uncomfortable invasive measurement and thereby also facilitates regular and more frequent measurement. Also, the measurement results are easily processed and the recurring costs are minimized. The measurement can be carried out without the consumption of analysis substances.

The sensitivity of the measurement method easily reaches 30 to 300 mg per dl. Dependencies of the measurement results on materials other than glucose, such as alcohol or drugs in the blood, are minimal or non-existent. The measuring device can be operated without learning or training costs and measurements can be carried out over sustained periods without calibration.

The following factors can be used separately or in combination when the present device and measuring method are implemented for use in glucose measurement:

A spectroscopy technique in the middle-infrared is used, in which glucose has a characteristic absorption spectrum (see FIG. 14). Here, for example, the entire spectral “fingerprint” of glucose can be covered. A pulsed quantum cascade laser or an alternative laser light source is used, which can cover a number of characteristic wavelengths.

The photothermal detection method described above is used (FIG. 15, FIG. 16).

The excitation and detection are adjusted in such a way that the absorption is measured in the interstitial fluid of the skin. The laser beam (excitation beam) penetrates up to 100 microns into the skin and reaches glucose molecules in the interstitial fluid of the skin. As a result of the absorption of light and the associated energy transfer, a thermal wave is generated, which in part, travels to the skin surface where it can be detected with the photothermal detection element described above. This makes use of a detection or interrogation laser beam, the deflection of which in the optical medium depends on the heating action of the thermal wave in the optical medium. The deflection is detected as an indicator for the absorption of the excitation beam by glucose.

When applied to the skin the excitation laser beam penetrates the stratum corneum, that is to say, the dead cells of the skin on the surface, which do not contain a current glucose level. The excitation beam reaches the stratum granulosum and stratum spinosum with relevant glucose components. The glucose levels in these layers directly follows the blood glucose level; the blood glucose level of interstitial fluid represents approximately 85-90% of the blood glucose level. This applies particularly to parts of the body that are well supplied with blood, such as the fingertips, thumbs, earlobes and lips. The material composition in the interstitial fluid is simpler overall than that in the blood, so that the interfering or distorting factors are lower for measurements in the interstitial fluid.

Certain distortions of the measurements due to variations in the outermost skin layers can also occur from subject to subject and are also time-varying.

In order to eliminate or minimize such distortions, measurement values are acquired from different skin depths (distance ranges to the skin surface). For this purpose, the infrared spectra for a plurality of modulation frequencies of the excitation beam (FIG. 17, FIG. 18) are determined and by combination of the spectra, are used to eliminate effects of upper layers of the skin.

As a result, the measurement method described for measuring glucose levels can compete with the current standard invasive methods in terms of accuracy and reliability (cf. FIG. 19).

FIG. 20 shows a measuring device similar to the one shown in FIG. 8, wherein the same reference numerals denote the same functional elements. This also applies to FIGS. 21, 22 and 23.

In FIG. 20 various temperature sensors 150, 151 and 152 are shown, which can be implemented individually or in groups or all in one measuring device, wherein the sensor 150 measures the temperature of the excitation transmission device 100, thus for example on a laser or a laser array, the temperature sensor 151 measures the temperature of an optical medium 108 and the temperature sensor 152 the temperature of a detection device, for example a photosensor. One or more of the measured temperature values can either be taken into account in the analysis of the material, by accounting for correction coefficients for the radiation intensity of the excitation transmission device, or for the detection sensitivity of the photosensor or other parts of the detection device in the evaluation. The correction coefficients may be given in the form of a calculation formula or be stored electronically in a table. However, it can also be provided, by means of a heating element 153 which can be arranged on the excitation transmission device 100, on the photosensor or, for example, on the optical medium, to use temperature regulation to keep the measuring device, wholly or partially, at a temperature which is higher than the ambient temperature and/or than the body temperature of a patient, so that a short-term temperature change due to heating under external influence is not a cause for concern.

FIG. 21 shows the use of a measuring device for measuring a urea concentration, wherein the excitation light wavelengths are selected such that they enable the detection of urea, thus for example, the absorption wavelengths of urea. The measuring can be performed on a part of the body, but also on a dialysis line 15 or a blood line of a dialysis machine. The corresponding line should then be firmly clamped to the optical medium.

FIG. 22 shows a measuring device with a moisture sensor 155, which is used to determine whether an object is placed on the optical medium 108. Only in the case of increased humidity or if the moisture value is detected in a specified value window, is the excitation transmission device enabled for operation, or turned on. This is intended to avoid the excitation radiation entering the environment more than necessary, even though it is essentially harmless. The switch actuated by the sensor 155 is labelled with 156.

At the same time, FIG. 22 shows a device for the suction of air 161, 162, 163, wherein 161 and 162 designate openings which end on the front of the optical medium and which are connected to a suction channel. This suction channel can extend e.g. in a circle around the region of the optical medium, which a body part is pressed against to perform a measurement. The suction openings can also be distributed in a circle. By means of the suction channel, the suction openings are connected to a vacuum suction device 163, for example in the form of a suction pump, during the operation of which an object pressed onto the optical medium is held in position or fixed there.

FIG. 23 shows a fixing device, which creates a hollow in the area of the optical medium into which e.g. a finger can be inserted. Alternatively or additionally, a locking clasp 165 can also be provided, which clamps the test object in place.

As shown in FIG. 23, the hollow is created by a circumferential raised edge 164, which can consist of an elastic material or a cushion, in particular an inflatable cushion. An inflatable cushion can also be provided, which can be inflated after the placement of a test object, in particular a finger, and when inflated, firmly clamps the object/finger in place. The measuring devices can be connected to a device for controlling the pressure in the cushion.

FIG. 23 also shows a pressure sensor 158, which can be arranged, for example, on the rear side of the optical medium, which is opposite the front side onto which an object to be measured is pressed. The sensor 158 can have, for example, a spring with a proximity switch/distance sensor and/or a piezoelectric sensor, which generates a signal as a function of the acting pressure and/or activates a switch 160 for turning the excitation transmission device on and/or off. Parallel to this, a luminosity sensor 157 is also shown in FIG. 23, which can be designed as a photosensor and which detects whether the front of the optical medium is covered by an object. In this case, the excitation transmission device is turned on or enabled by means of the switch 159, otherwise it can be disabled.

FIG. 24 shows two depth profiles recorded or determined with the method according to the invention and a device according to the invention, of the density of two substances which are located in the material/body part to be examined. The two substances are identified by excitation beams with different wavelengths/groups of wavelengths, wherein for the wavelengths for example, one or more wavelengths can be chosen, in which or in the vicinity of which absorption maxima of the substances to be identified are located. The measuring method according to the invention can be used to determine density distributions 166, 167 I(T) of the two substances as a function of the depth T, measured perpendicular to the surface. The substances will typically have identical or different density distributions. If the density distribution 166 of a reference substance is known, or only the depth T1 at which the maximum 166 a or other characteristic point of the distribution 166 is located under the surface, then the density distribution 167 of the other substance or the location T2 of the maximum density of its distribution can be calibrated to this reference value.

The present property rights application (as already mentioned), in addition to the subject matter of the claims and exemplary embodiments described above, also relates to the following aspects. These aspects can be combined individually or in groups, in each case with features of the claims. Furthermore, these aspects, whether taken alone or combined with each other or with the subject matter of the claims, represent stand-alone inventions. The applicant reserves the right to make these inventions the subject matter of claims at a later date. This can be done either in the context of this application or else in the context of subsequent divisional applications or continuation applications claiming the priority of this application.

Other detection methods for the detection of a response signal after emission of an excitation beam may comprise:

-   -   photo-acoustic detection—photo-acoustic detection using a tuning         fork or other vibration element or: a slightly modified form of         photo-acoustics with an open QePAS cell (Quartz-enhanced         Photo-Acoustic Spectroscopy). These methods can be used to         detect pressure fluctuations/vibrations on the surface and         evaluate them in the manner described above for the measured         beam deflection.

In principle, measured values of a phase shift of the response signal relative to a periodic modulation of the excitation beam can be used for depth profiling. (To this end, warming/cooling phases of the material surface should be more accurately evaluated with regard to their waveform or pattern.)

The device described can be associated with a supply of adhesive strips for removing dead skin layers, in order to allow a maximally undistorted measurement on a human body, as well as plasters with thermal conductive paste that can be applied to the optical medium on a regular basis. The optical medium can be replaceable, given suitable fastening and adjustment of the remaining parts.

To perform the measurement, the device can be provided and configured not only on a person's finger, but also on a lip or an earlobe.

In some embodiments the measurement can work even without direct contact and placement of the finger or other part of the body (at a distance), resulting in a contact-free measurement.

The measurement can be improved with regard to its accuracy and reliability by combination of a plurality of the measuring systems described and explained, with similar susceptibility to error.

DAQ and lock-in amplifiers in the evaluation can be combined in one device and overall the evaluation can be digitized.

The measuring device can also be performed on a moving surface, so that in the course of a grid measurement: excitation light source and and/or measuring light source move over the skin in a grid pattern during the measurement, which allows skin irregularities to be compensated for or even eliminated.

The sensitivity of the detection device/deflection unit can be optimized by adjustment/variation of the wavelength of the probe beam/measurement light source. For this purpose, the measurement light source can be varied with respect to wavelength or else contain a plurality of laser light sources at different wavelengths for selection or combination.

For the deflection of the pump/probe laser an ideal transverse mode (TEM) can be selected.

The excitation transmission device, measuring light source and detector can be configured as a common array and the beams can be suitably deflected in the optical medium to concentrate the emission and reception of all beams at one point.

A lens on or in the crystal of the optical medium can contribute to deflecting the measuring light beam more strongly depending on the response signal.

In addition, it is conceivable to use a gap-free photodiode for the detection, and a lens could then focus the measuring light beam after its exit, to thus enable a more accurate measurement.

An additional variant of the invention, in accordance with the patent claims is described in the following concept. This concept, whether taken alone, in combination with the above aspects or with the subject matter of the claims, also constitutes at least one independent invention. The applicant reserves the right to make this invention or these inventions the subject of claims at a later date. This can be done either in the context of this application or else in the context of subsequent divisional applications or continuation applications claiming the priority of this application:

A concept for non-invasive blood sugar measurement by a determination of the glucose in the skin by means of excitation using quantum-cascade lasers and measurement of the thermal wave by radiant heat. On the basis of FIGS. 12 and 13 a method is described with which the concentration of the glucose or another material in the interstitial fluid (ISF) in the skin can be determined. Glucose in the ISF is representative of blood glucose and follows it rapidly in the event of changes. The method consists of at least individual steps or groups of the following steps or of the entire sequence:

1. The point on the skin 102 (in this case, the first region of the material surface), is irradiated with a beam of a quantum cascade laser, which is focused and possibly reflected at a mirror or parabolic mirror 140, and which is incrementally or continuously tuned over a specific infrared range, in which glucose is specifically absorbed. Instead of the quantum cascade laser 100, a laser array with a plurality of lasers radiating at single wavelengths can also be used. The spectral range (or the individual wavelengths, typically 5 or more wavelengths) can be in particular between approximately 900 and approximately 1300 cm⁻¹, in which glucose has an absorption fingerprint, that is to say, typical and representative absorption lines. 2. The excitation beam designated with SA is employed continuously (CW lasers) or in pulsed mode with a high pulse repetition rate or in a modulated manner. In addition, the excitation beam is low-frequency modulated, in particular in the frequency range between 10 and 1000 Hz. The low-frequency modulation can be performed with a variety of periodic functions, in various embodiments sine-wave, square wave or sawtooth wave, or the likes. 3. Due to the irradiation of the skin the IR-radiation penetrates the skin to a depth of roughly 50-100 μm and—depending on the wavelength—excites specific vibrations in the glucose molecule. These excitations from the vibration level v0 to v1 return to the initial state within a very short time; in this step heat is released. 4. As a result of the heat produced according to (3) a thermal wave is formed, which propagates isotropically from the place of absorption. Depending on the thermal diffusion length, defined by the low-frequency modulation described in (2) above, the thermal wave reaches the surface of the skin periodically at the modulation frequency. 5. The periodic emergence of the thermal wave at the surface corresponds to a periodic modulation of the thermal radiation property of the skin (material surface of the sample). The skin can be described here approximately as a black body radiator, whose entire emission according to the Stefan-Boltzmann law is proportional to the fourth power of the surface temperature. 6. With a detector 139 for heat radiation, i.e., an infrared detector, i.e. a thermocouple, bolometer, semiconductor detector or similar device, which is directed at the point of the skin under irradiation, the periodic temperature increase described under (5) is recorded. It depends on the irradiation of infrared light described under (1) and (2), and on the absorption described under (3), and therefore depends on the concentration of glucose. The thermal radiation SR (in this case, the response signal) is collected by means of an optical element, in one embodiment an infrared lens or a mirror, in particular a concave parabolic mirror 141, and, in one embodiment is directed via a convex mirror 141 a on to the detector 139. For this purpose a collection mirror used in one embodiment can have an opening 142, through which the collected beam is directed. A filter 143 can also be provided in the beam path, which only allows infrared radiation of a certain wavelength range to pass. 7. In processing the response signals, the modulation frequency can be specifically taken into account, for which the response signal can be processed in a lock-in amplifier 144. By analysis of the phase angle between the excitation signal and heat radiation signal (response signal) using a control and processing unit 147, the depth information relating to the depth below the surface can be obtained, from which the response signals are largely obtained. 8. The depth information can also be obtained by the selection and analysis of various low-frequency modulation frequencies as described in (2) for the excitation beam and the combination of the results for different modulation frequencies (wherein the results can also be weighted differently for different modulation frequencies). Difference methods or other calculation methods can be used for this, to compensate for the absorption of the topmost skin layers. 9. To maximise the sensitivity in the detection of the thermal radiation according to point (6), it is used over a broad spectral band for the entire available infrared range. As many regions of the Planck radiation curve as possible should be used. To make the detection insensitive to the intensive excitation radiation, the detection of the heat radiation is provided with blocking filter (notch filter) 143 for these excitation wavelengths. The wavelength range 148 transmitted through the blocking filter 143 is also apparent from the diagram of FIG. 13. Therein, the intensity of the response signal is shown both as a function of the wavelength, in a first (solid) curve 145 without an excitation beam or only with excitation radiation in non-specific wavelengths for the material to be identified (i.e. without the wavelengths where specific absorption bands of the material exist), and then in a second (dashed) curve 146 a similar curve is shown, wherein an excitation beam is irradiated which contains specific absorption wavelengths of the material to be identified. 10. From the thermal signal measured according to (6-9), which is dependent on the excitation wavelength, if glucose is to be identified, in one embodiment the background is determined first with non-glucose-relevant wavelengths (or excluding them) of the excitation beam (curve 145), and then with (or including) the glucose-relevant wavelengths the difference from the background signal is determined. This results in the glucose concentration in the skin layer or skin layers, which are defined by the selected phase position according to (7) or the different modulation frequencies according to (8) or a combination of these.

Although the invention has been illustrated and described in greater detail by means of preferred exemplary embodiments, the invention is not limited by the examples disclosed and other variations can be derived therefrom by the person skilled in the art without departing from the scope of protection of the invention.

LIST OF REFERENCE NUMERALS

-   10 device -   100 excitation transmission device/excitation light source -   100 a emitters/transmission elements -   101 material -   102 first region -   103 volume -   104 device -   105 device -   106 detection device -   107 processing device/evaluation device -   107 a memory -   108 optical medium -   108 a surface section -   108 b surface section -   109 adjustment device -   110 partial surface -   111 partial surface -   112 measuring beam/measuring light beam -   113 mirror surface -   114 mirror surface -   116 opening -   117 opening -   118 opening -   119 connector body -   120 fibre-optic cable -   121 support -   122 housing -   123 body -   124 side -   125 belt -   126 fingertip -   127 adjustment device -   128 imaging optics -   129 imaging optics -   130 optical detector/camera -   131 data processing device -   132 controller -   133 micro-mirror -   134 micro-mirror -   135 micro-electro-mechanical system -   136 deflection device -   137 control device -   138 layer -   139 infrared detector -   140 mirror -   141 parabolic mirror -   142 opening in 141 -   143 wavelength filter -   144 lock-in amplifier -   145 signal curve of the response signal (solid line) -   146 signal curve of the response signal (dashed line) -   147 control and processing device -   148 wavelength range -   BZA blood sugar level indication -   D detection result -   GF interface -   SA excitation beam -   SR response signal 

1. A device for analysing a material having an excitation transmission device for generating at least one electromagnetic excitation beam with at least one excitation wavelength, wherein said excitation transmission device is a laser light source, a detection device for detecting a response signal and a device for analysing the material on the basis of the detected response signal, wherein the device comprises an optical medium, which is in direct contact with the material in a first region of the surface of the material, the excitation transmission device radiates the at least one electromagnetic excitation beam into a material volume, which is located underneath a first region of the surface of the material, the device comprises a system for emitting a measuring beam, which is arranged so that the emitted measuring beam penetrates the optical medium, which optical medium is made of a material that is transparent for the measuring beam, and in particular of glass, of crystal or a transparent plastic, wherein the measuring light beam and the excitation beam are directly adjacent or overlapping on the interface between the optical medium and the material surface, at which the measuring light beam is reflected, wherein the detection device is a device for receiving said reflected measuring beam forming said response signal and/or for directly or indirectly detecting a deflection of the reflected measuring beam, and the system for emitting a measuring beam and the detection device are aligned with respect to each other in such a way that the detection device detects the measuring beam as a time-dependent response signal, after this beam has been reflected at least once at the interface of the optical medium, which is in contact with the material in the first region of the surface of the material, and wherein the device comprises a device for the intensity modulation of the excitation light beam with one or more frequencies, the detection device is configured for detecting the time-dependent response signal as depending on the wavelength of the excitation light and the intensity modulation of the excitation light, and with a processing unit for determining response signals as depending from the phase position of the respective response signal in relation to the phase of the modulation of the excitation beam, and for determining an intensity distribution of the response signals as a function of the depth underneath the surface, in which the reaction signals are generated, based on the phase position of the response signals in relation to the modulated excitation beam at one or various modulation frequencies of the excitation beam.
 2. The device according to claim 1, wherein the excitation transmission device is directly—or indirectly by means of an adjustment device—mechanically fixedly connected to an optical medium which is in direct contact with the material, in particular with the first region of the surface of the material.
 3. The device according to claim 1, wherein the device for the intensity modulation comprises or is formed by an electrical modulation device, which is electrically connected to the excitation transmission device and electrically controls it, or comprises at least one controlled mirror arranged in the beam path, or comprises at least one layer which is arranged in the beam path and is controllable with respect to its transparency, or is formed by such a layer
 4. The device according to claim 1, wherein the device for emitting a measuring beam and/or the detection device and/or the excitation transmission device are directly mechanically fixedly connected to the optical medium and/or coupled to the same by means of a fibre-optic cable.
 5. The device according to claim 1, wherein the optical medium directly supports an imaging optics, and/or an imaging optics is integrated into the optical medium.
 6. The device according to claim 1, wherein the surface of the optical medium has a plurality of partial faces inclined towards each other, at which the measuring beam, in particular the measuring light beam, is reflected multiple times.
 7. The device according to claim 1, wherein the device is configured to detect the temporal waveform of the response signal and subject it to a Fourier transformation, preferably after an excitation pulse of between 10 ms and 1000 ms duration, more preferably between 50 and 500 ms, further preferably between 50 and 150 ms duration.
 8. The device according to claim 1, wherein the device is configured such that the measurement is repeated sequentially at different incidence angles of the excitation beam, and the results are combined with each other, in particular subtracted from each other, in order to eliminate the effects of the upper layers of the skin.
 9. A Method for analysing a material, using a device according to claim 1, wherein with an excitation transmission device, at least one electromagnetic excitation beam with at least one excitation wavelength is generated by an at least partially simultaneous or consecutive operation of a plurality of laser emitters of a laser light source, the excitation transmission device radiates the at least one electromagnetic excitation beam into a material volume, which is located underneath a first region of the surface of the material, using a device, an intensity modulation of the excitation beam is carried out, and using a detection device, a time-dependent response signal is detected as dependent on the wavelength of the excitation light and/or the intensity modulation of the excitation light, wherein a device for emitting a measuring beam emits a measuring beam into an optical medium which is made from a material that is transparent for the measuring beam, and in particular from glass, crystal or a transparent plastic and that is in direct contact with the material in a first region of the surface of the material, and wherein with a detection device, which is a device for receiving said reflected measuring beam forming said response signal and/or for directly or indirectly detecting a deflection of the reflected measuring beam, a response signal is detected, and the device for emitting a measuring beam and the detection device are aligned with respect to each other in such a way that the detection device detects the measuring beam as a time-dependent response signal, after this beam has been reflected at least once at the interface of the optical medium, which is in contact with the material in a first region of the surface of the material, using the detected response signal the material is analysed by measuring the time behaviour of the response signals in a phase-sensitive manner while the intensity of the excitation beam is periodically varied, and an intensity distribution of the response signals as a function of the depth underneath the surface, in which the response signals are generated, is determined from the phase position of the response signals in relation to the modulated excitation beam for one or for a plurality of excitation beams.
 10. The method according to claim 9, wherein using different modulation frequencies of the excitation transmission device, response signals, in particular temporal response signal waveforms or patterns for different wavelengths of the excitation beam, are successively determined and a plurality of response signal waveforms or patterns at different modulation frequencies are combined with each other, wherein, in particular, specific information for a depth range under the surface is obtained from this.
 11. The method according to claim 9, wherein when a plurality of modulation frequencies of the pump beam are used at the same time, the detected signal is resolved into its frequencies by means of an analytical procedure, preferably a Fourier transform, and only the partial signal that corresponds to the desired frequency is filtered out.
 12. The method according to claim 9, wherein as a function of a material concentration identified in the material, a dosing device is activated for delivering a substance into the material, in particular into a body of a patient, and/or an acoustic and/or visual signal is output and/or a signal is delivered to a processing device via a wireless connection.
 13. The method according to claim 9, wherein the measurement, which comprises the detection of the response signal at at least one modulation frequency or in a time-resolved manner after a transmission pulse and at one or more wavenumbers, is repeated successively at different incidence angles of the excitation beam and the results are combined with each other, in particular subtracted from each other, in order to eliminate the effects of the upper layers of the skin.
 14. The method according to claim 9, wherein the temperature of the laser emitter(s) of the excitation transmission device and/or the temperature of the detection device, in particular of an optical medium and/or a detection radiation source and/or an optical sensor, is kept constant during the analysis, in particular is kept constant at a specified temperature, more particularly at a specified temperature above the temperature of the human body, more preferably above 37 degrees Celsius, more preferably above 38 or 40 degrees Celsius.
 15. The method according to claim 9, wherein the excitation beam is modulated with between 0 and 10 modulation frequencies, preferably with between 0 and 5 modulation frequencies, more preferably with between 1 and 3 modulation frequencies, more preferably with only one modulation frequency, and the time characteristic of the response signal, in particular a phase-sensitive characteristic of the response signal is analysed. 